ECM-Syndecan-4-FAK signaling is associated with epithelial invagination and buccolingual asymmetry during mandibular molar development.

Introduction: Tooth morphogenesis in mice provides valuable insights into the cellular and molecular mechanisms governing organ shape. During the critical transition from the dental placode to the early cap stage (E12.5-E14.5), epithelial invagination and shape changes are accompanied by complex cellular rearrangements, including suprabasal intercalation and collective cell behaviors. This study examined how Syndecan-4 (Sdc4), focal adhesion kinase (FAK), and basement membrane-related interactions are deployed during early mandibular first molar development. Methods: We performed a stage-matched reanalysis of publicly available single-cell RNA-seq datasets, together with morphometric and spatial validation, to characterize epithelial state changes across E12.5-E14.5. Results: At E12.5, DE-like epithelial cells displayed a proliferative odontogenic program enriched for cell-cycle regulators and key signaling pathways, including Wnt and Hippo. By E13.5, extracellular matrix components, including collagen, laminin, and agrin, together with focal adhesion-related pathways, became prominent in association with epithelial remodeling. At E14.5, upregulation of adhesion and structural scaffold components was consistent with tissue stabilization during morphogenesis. Across these stages, the data suggest a temporal shift from proliferative odontogenic activity to ECM-adhesion remodeling and then to tissue stabilization during early molar morphogenesis. Discussion: Integrating the transcriptomic, morphometric, and spatial findings, we propose that an ECM-Sdc4-FAK-related signaling axis may contribute to epithelial invagination and the emergence of buccolingual asymmetry. More broadly, these findings highlight cell-matrix interactions as an important component of the early tooth morphogenetic environment, while functional perturbation studies will be needed to establish direct causality.